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Alpha-1-Antitrypsin Deficiency, AAT - PI

Clinical Features

Alpha-1-antritrypsin (AT) is a protease inhibitor (PI) which inhibits the activity of neutrophil elastase, the key enzyme for degrading elastin from alveolar walls of the lung and other tissues such as the liver.

Depending on the serum levels of alpha-1-AT which are critical below 20% of normal, deficiencies of alpha-1-AT lead to a higher frequency of chronic obstructive pulmonary disease (COPD) and, consequently, to emphysema. In the most important type of disease PI-ZZ (cf. genetics), onset and severity of pulmonary disease vary in an inter- and intrafamilial manner. Additional genetic and environmental factors affect disease manifestation and progression. Emphysemas are predominant in adulthood, but extremely seldom in infancy. Non-smokers with deficiency type ZZ are affected by dyspnea at an average age of 45 to 50 years, smokers at age 35.

Cellular necroses, fibrosis and cirrhosis of the liver are the second complication of alpha-1-AT-deficiency. Approximately 18 % of all children with type ZZ are affected by liver symptoms such as prolonged neonatal jaundice, hyperbilirubinemia, elevated transaminases or hepatosplenomegaly. Severe liver symptoms in childhood are rare. Approximately 20 % of all patients above age 50 with type ZZ exhibit liver cirrhosis.

Genetic Information

Alpha-1-AT deficiency is inherited as an autosomal recessive disorder. Up to now, there are more than 70 different mutations known in the PI (protease inhibitor 1) gene on chromosome 14 (14q32.1) which also corresponds to the different electrophoretic variants. Approximately 92 % of the normal middle European population carries the genotype PI-MM. Approximately 7 % of the population carry one allele with a deficiency type allele (PI-MS or PI-MZ) or a silent allele (PI-MO), which is only rarely associated with any relevant lung or liver symptoms. Clinical symptoms usually occur with mutations on both alleles (e.g. PI-ZZ or PI-SZ). Deficiency type PI-ZZ results in reduced alpha-1-AT serum levels of around 15 to 20 % of normal values and is therefore most frequently associated with clinical symptoms.

Prevalence

Deficiency type PI-ZZ approximately 1 : 6 000 - 7 000
Heterozygosity for the Z allele (PI-MZ) affects around 2-5 % of the normal population

Diagnostic